The need for effective therapeutic treatment of patients has resulted in the development of a variety of pharmaceutical formulation delivery techniques. One traditional technique involves the oral delivery of a pharmaceutical formulation in the form of a pill, capsule, elixir, or the like. However, oral delivery can in some cases be undesirable. For example, many pharmaceutical formulations may be degraded in the digestive tract before the body can effectively absorb them.
In such inhalation techniques, aerosol is added to the inspiratory gas by placing a T-piece or equivalent in the circuit and entraining the aerosol with the inspiratory gas. In such arrangements the aerosolization device is downstream of the gas source and upstream of the patient. Inhalable drug delivery, also known as pulmonary delivery, where a patient orally or nasally inhales an aerosolized pharmaceutical formulation to deliver the formulation to the patient's respiratory tract, may also be effective and/or desirable. In some inhalation techniques, an aerosolized pharmaceutical formulation provides local therapeutic treatment and/or prophylaxis to a portion of the respiratory tract, such as the lungs, to treat respiratory diseases such as asthma and emphysema and/or to treat local lung infections, such as fungal infections and cystic fibrosis. In other inhalation techniques, a pharmaceutical formulation is delivered deep within a patient's lungs where it may be absorbed into the bloodstream for systemic delivery of the formulation throughout the body.
Many types of aerosolization devices exist including devices comprising a pharmaceutical formulation stored in or with a propellant, devices that aerosolize a dry powder, devices which use a compressed gas or other mechanism to aerosolize a liquid pharmaceutical formulation, and similar devices.
One known aerosolization device is commonly referred to as a nebulizer. A nebulizer comprises a container having a reservoir that contains a fluid, liquid, or liquefiable formulation. If liquid, the pharmaceutical formulation generally comprises an active agent that is either in solution or suspended or dispersed within a liquid medium. Various medicaments available in liquid form may be aerosolized for use in therapies. Any suitable medicament, therapeutic agent, active substance or pharmaceutically active compound than can be nebulized may be employed. It can also act to deliver any agent presented in an aqueous drug solution. Where the liquid being aerosolized is water, saline or other solution of water or saline, the aerosol generator also provides additional humidity to the circuit which may enhance patient comfort where no other humidity source is present.
Energy is introduced into the reservoir to aerosolize the liquid pharmaceutical formulation to allow delivery to the lungs of a patient. In one type of nebulizer, generally referred to as a jet nebulizer, compressed gas is forced through an orifice in the container. The compressed gas forces liquid to be withdrawn through a nozzle, and the withdrawn liquid mixes with the flowing gas to form aerosol droplets. A cloud of droplets is then administered to the patient's respiratory tract. In another type of nebulizer, generally referred to as a vibrating mesh nebulizer, energy such as high frequency ultrasonic waves are generated to vibrate a mesh. This vibration of the mesh aerosolizes the liquid pharmaceutical formulation to create an aerosol cloud that is administered to the patient's lungs. Vibrating mesh technology generates an aerosol with a precisely controlled particle size range optimized in general respiratory use for deep lung deposition. The distribution of particles can be represented as a normal distribution with the majority of particles produced in the range 2-10 microns. Such technology is described in detail in U.S. Pat. No. 8,418,690, Col. 9, lines 8-48, the subject matter of which is expressly incorporated by reference. Furthermore, functions such as control of the nebulizer are described in detail in U.S. Pat. No. 8,418,690, Col. 9, line 58—Col. 11, line 38, the subject matter of which is expressly incorporated by reference.
In still another type of nebulizer, ultrasonic waves are generated to directly vibrate and aerosolize the pharmaceutical formulation.
The valves, devices, fittings, systems, components and adapters for introducing aerosols into a patient in need of such introduction may also be suitably used with dry powder administration devices, such as passive dry powder inhalers and active dry powder inhalers. A passive dry powder inhaler comprises an inhalation device which relies upon a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does not include inhaler devices which comprise a means for providing energy, such as pressurized gas and vibrating or rotating elements, to disperse and aerosolize the drug composition. An active dry powder inhaler comprises to an inhalation device that does not rely solely on a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does include inhaler devices that comprise a means for providing energy to disperse and aerosolize the drug composition, such as pressurized gas and vibrating or rotating elements.
Nebulizers are often used to deliver (1) an aerosolized pharmaceutical formulation to a hospitalized or non-ambulatory patient; and/or (2) large doses of aerosolized active agent; and/or (3) an aerosolized pharmaceutical formulation to a child or other patient unable to receive a dry powder or propellant based pharmaceutical formulation.
Nebulizers are useful for delivering an aerosolized pharmaceutical formulation to the respiratory tract of a patient who is breathing via a nasal cannula. But there are problems associated with the introduction of aerosolized pharmaceutical formulation via nasal cannulas. For example, crashout of the pharmaceutical formulations onto the interior of the apparatus decreases the efficacy of the treatment.
US patent publication no. US20060120968A1 teaches crashout reduces the quantities of the aerosolized material reaching the lungs because of inefficient delivery to the lungs. A significant contributor to extrathoracic losses is material deposited at or around the nasal prongs or nasal cannula where there is potential to clog the prongs during extended treatments.
Devices in the prior art require filters to prevent crashout, but the efficacy of the treatment is reduced. International PCT patent application publication no. WO2008116165A2, by Lemahieu et al., disclose methods and systems of delivering medication via inhalation. The system utilizes a particle filter to limit particle deposition, aka crashout, on the walls of the mask and any air hose used with the device. US patent application publication no. US20070267010A1, by Fink et al., discloses an inspiratory filter that removes aerosolized droplets.
Devices in the prior art minimize corners and shorten the delivery system in an effort to prevent efficacy reduction due to crashout. US patent application publication no. US20110011395A1, by Mazela et al., discloses a device with an aerosol flow channel formed into a funnel-like shape that minimizes corners, and thus helps to prevent the accumulation of deposits within the adaptor. The '395 published patent application also teaches preferably, the aerosol tube is expandable to secure the optimized placement of the nebulizer, for example, as close to the patient as possible but in comfortable location to avoid restriction of any nursing procedures and allow patient for some head motion. Expandable tubes help avoid creation of sharp angles and thus avoid potential aerosol deposition, aka crashout, within the delivery system.
US patent application publication no. US20070083677A1, by Cecka et al., discloses devices, including adapters, for endobronchial therapy that include nasal delivery, cannulas, and delivery of aerosols. The '677 teaches nasal administration of an aerosol at an air flow rate of 60 L/min and is silent regarding crashout.
US patent application no. US20170304565A1, titled “Inhalation device for use in aerosol therapy of respiratory diseases”, by Koen Allosery et al., discloses an inhalation device for use in aerosol therapy of respiratory diseases. The device comprises a face mask with a vibrating mesh nebulizer and a valve insertable in the flow channel of the suction device through the lateral openings. The flow channel facilitates low and laminar flow through the device.
The device can be connected to a gas source via an opening in the flow channel, and results in a lower flow. The flow channel extends from the gas inlet opening to the aerosol inlet opening of the face mask. The flow channel facilitates a certain flow resistance of an aerosol flow rate of 1 to 20 L/min in between the gas inlet opening and the inlet opening of the face mask. The upstream portion of the flow channel comprises the portion from the gas inlet opening (and including) the nebulizer, the segment to the lateral opening that allows 1 to 20 L/min constant flow rate, and in particular, from about 1 L/min to about 5 L/min. The flow channel size and shape are configured to achieve a laminar flow of gas conducted through the flow channel at a constant flow rate.
Regarding the flow channel, the '565 published patent application also teaches a sudden change in diameter has to be avoided, and it is preferred than the inner wall is formed of a material having a smooth inner wall surface. An example of suitable upstream segment is a regular cylindrical pipe formed of an inert polymeric material having a polished stainless steel or a smooth surface. The '565 published patent application also teaches the gas inlet opening is formed of a tube fitting, to facilitate attachment of a gas source, substantially such as stainless steel, and to allow laminar flow of inert gas. The gas inlet opening is also formed of a smooth material. For example, it is more advantageous to use a tube fitting having a shaped inner wall that is smooth and cylindrical in order facilitate laminar flow of gas.
The substantially laminar flow refers to a Reynold's number of about 2300 or less (Reynold's number). Preferably, the upstream segment of the flow channel has a size and shape to achieve a Reynolds number of not more than 2000 in 1 to 5 L/min flow rate. The '565 published patent application teaches, in particular, when the gas flow rate is 1 to 5 L/min at the gas inlet, it allows the creation of a slight over-pressure in the face mask. The over-pressure facilitates inhalation by the patient of the aerosol spray generated by the device. The over pressure allows for a normal breathing pattern, substantially without interference, and effective drug delivery.
Regarding laminar flow, US patent application publication no. US20180104424A1, titled “Inhaler and Methods of Use Thereof”, by Henri Akouka et al., discloses a medicament delivery device comprises a dosing chamber configured to contain dry powder medicament and a channeling means to conduit air flow. The '424 published patent application teaches that a consistent cross-sectional area throughout the upper flow path may promote a laminar air flow through the upper flow path. Alternatively, the cross-sectional area of the upper flow path may vary along its length, but laminar air flow is still promoted as long as a minimum cross-sectional area is met, for example, at least about 40 mm2, at least about 50 mm2 or at least about 60 mm2. Furthermore, the '424 published patent application discloses that the exit channel and dosing chamber are aligned to promote a laminar flow of the aerosolized pharmaceutical out of the dosing chamber and through the exit channel.
US published patent application no. US20180021530A1, by Fink et al., discloses the aerosolization device may include a conduit, an aerosol generator, a restrictor disposed within the conduit, and an indicator mechanism. The restrictor defines a plurality of apertures disposed along an outer periphery of the restrictor configured to provide a relatively laminar flow downstream of the restrictor compared to upstream of the restrictor. The '530 published patent application teaches that laminar flow provides a consistent velocity field to deliver the aerosolized particles to the user's respiratory system in a consistent manner while minimizing impactive losses; additionally, the laminar flow minimizes an amount of aerosolized medicament that may be deposited on a wall of the conduit. The exemplary embodiments in the '530 published patent application teach flow rates between 5 and 14 L/min, but the '530 is silent regarding low flow.
U.S. Pat. No. 5,355,872 A, by Riggs et al., discloses a low flow rate nebulizer apparatus and method of nebulization. A nebulizer device, comprising: (a) a housing defining an interior volume, including a reservoir portion for holding medicament for entrainment into a carrier gas to form a delivery gas mixture comprising nebulized medicament and carrier gas; (b) a discharge port connected to the housing in flow communication with the interior volume, for discharging the delivery gas mixture from the housing; (c) a jet passage member having (i) an inlet portion for introduction of carrier gas and (ii) a nozzle portion positioned in the interior volume of the housing for discharging carrier gas in jet form in the interior volume, for entrainment of medicament from the reservoir portion of the housing in the carrier gas jet, such nozzle portion comprising a nozzle orifice accommodating carrier gas flow, wherein the nozzle orifice has an equivalent orifice diameter in the range of from about 0.005 inch to about 0.020 inch. The '872 patent teaches a low flow rate nebulization method comprising flowing the carrier gas through the jet passage member in the range of from about 0.5 to about 3.25 liters per minute, to disperse the medicant into the carrier gas and form a pulmonarily effective nebulized medicant in the carrier gas, as a medicant/carrier gas mixture. At flow rate values below about 0.5 liters per minute, the volumetric flow rate of carrier gas tends to become insufficient to achieve good dispersion of the medicant in the flowing gas stream. At volumetric flow rate values above about 3.25 liters per minute, the small-size orifice dimensions employed in the practice of the invention tend to produce a back pressure which renders it disproportionately more difficult to achieve a reliable coupling and seal between the inlet portion of the jet passage member and the associated carrier gas flow means.
U.S. Pat. Nos. 8,418,690 and 9,572,950, and U.S. published patent application number 2017/0182279 by Power et al., disclose a supplemental oxygen delivery system which aerosol generator 9 delivers aerosol into an oxygen stream 13 flowing between an inlet 14 and an outlet 15 of the housing 10 or 30 which sits in the circuit from the supplemental oxygen supply to a patient via a nasal cannula 3 or a face mask 4. Housing 10 is designed to selectively allow only smaller aerosol particle sizes (less than 3 microns), suitable for transport along narrow bore tubing, onto to the patient while encouraging localized deposition of the aerosol heavier particles. Housing 10 also has a removable plug 16 in the base 17 thereof for draining any liquid that accumulates in the housing 10. As illustrated in FIG. 19 and Example starting in Col. 6, line 32, more than fifty percent of the aerosol particles, specifically the particles larger than the Volumetric Mean Diameter (VMD or Dv50) are removed from the distribution and are drained as liquid from housing 10.
There remains a need for more effective adapters for introducing aerosols at low flow into nasal cannulas without crashout. Accordingly, there also remains a need for improved methods of treatment and/or prevention that use such adapters.